Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV

MicroRNA-29 specifies age-related differences in the CD8+ T cell immune response

MicroRNAs (miRNAs) have emerged as critical regulators of cell fate in the CD8+ T cell response to infection. Although there are several examples of miRNAs acting on effector CD8+ T cells after infection, it is unclear whether differential expression of one or more miRNAs in the naive state is consequential in altering their long-term trajectory. To answer this question, we examine the role of miR-29 in neonatal and adult CD8+ T cells, which express different amounts of miR-29 only prior to infection and adopt profoundly different fates after immune challenge. We find that manipulation of miR-29 expression in the naive state is sufficient for age-adjusting the phenotype and function of CD8+ T cells, including their regulatory landscapes and long-term differentiation trajectories after infection. Thus, miR-29 acts as a developmental switch by controlling the balance between a rapid effector response in neonates and the generation of long-lived memory in adults

Nāgas and Relics

Surveys the moral world illumined by this particular reading of the Mahāvaṃsa, and the role of the especially salient character of the nāgas in that world. This chapter argues that the nāgas drive the entire narrative arc of the text, beginning with the initiatory, physical visit of the Buddha, their successful conversion by the Buddha himself, through the acquisition, enshrinement, and right veneration of his relics. This chapter goes on to show how the textual community envisions the world without the enduring, living presence of the Buddha, where relics are a viable technology developed by a community seeking continues proximity to the Buddha. Nāgas are utilized as particularly salient characters to facilitate the ongoing connection with the Buddha as they help determine the value of relics, they locate and guard relics, they are simultaneously model worshippers and unworthy hoarders of relics, and they mark time and recall the Buddha by becoming relics. After exploring the tripartite classification of relics operative in the early medieval textual community responsible for the Mahāvaṃsa, we will investigate the nāgas’ relationships to relics of use (pāribhogika), corporeal relics (sarīrika), and representation or image relics (uddesika).</p

Nāgas, Transfigured Figures Inside the Text, Ruminative Triggers Outside

The useful snakelike character nāga drives the opening narrative of the Mahāvaṃsa: the fighting family of nāgas in fact provokes the Buddha’s visit to the island, and the invitation of a converted nāga prompts his subsequent return. This chapter defines and situates the nāga in Pāli Buddhist literature, especially in the case of the Bhūridatta Jātaka where the Buddha himself, in a previous birth, was a nāga. Crucial here are the various indications of its slippery ontological nature and thus the soteriological repercussions: nāgas are agents both in our world and in the Nāgaloka; the nāga is a chthonic inhabitant of/mover on the waters, a salient vehicle for the movement of the dhamma from India to a new center, Sri Lanka, because they are an accepted part of the pan-Indic cosmos and yet are presented in the Sri Lankan context as autochthonous; they are karmically challenged because of their lack of human birth and yet they are always seen in proximity to the Buddha or his relics. Nāgas are liminal: neither human nor fully animal, these semi-divine agents are nonetheless capable of converting to Buddhism and are in fact key agents in the transmission of the dhamma, particularly to border regions. Nāgas are critical characters to effectively transfer the sāsana to Sri Lanka, just as they are critical characters to provoke the correct emotional states called for by the text; as characters, nāgas provoke the requisite imaginative capacity for the ethical transformations in readers called for by the text.</p

Instructions, Admonitions, and Aspirations in Vaṃsa Proems

If we read the proem, or opening poem of reading instructions, of the Mahāvaṃsa, especially in light of the proem of the earlier related text Dīpavaṃsa, we see that the traditional, historicizing, scholarly way of reading and using the Mahāvaṃsa misses the point: the Mahāvaṃsa is intended to effect a transformation in the reader/hearer through the cultivation of the highly prized Buddhist emotions of saṃvega (anxious thrill) and pasāda (serene satisfaction). The proems straightforwardly articulate the ethically transformative potential of the texts, a potential realized through proper reading by an appropriate audience (of “good people”). Following subtle and blatant cues within the text, this chapter considers a way to read the Mahāvaṃsa as literature, a corrective to the predominant historicizing focus, where the proem prepares a particular kind of reader and circumscribes a particular kind of textual community to help not only individual ethical transformation, but also to envision the Buddhist landscape with Sri Lanka at the center.</p

Historicizing (in) the Pāli Dīpavaṃsa and Mahāvaṃsa

Scholars and Buddhists alike have treated the Mahāvaṃsa as a history, provoking all the concomitant responsibilities and expectations and methods of interpretation assumed to be at work when one does (or reads and interprets) history. This chapter suggests that one of the primary concerns for the fourth and fifth century Mahāvihāran monks responsible for compiling the Dīpavaṃsa and Mahāvaṃsa was to provide a vehicle for the continued presence and proximity of the Buddha through evocative, transformative literature. The vaṃsa thus works on the reader/interpreter in ways not entirely unlike the way history works on the modern scholar, but there is a significant difference. The Mahāvaṃsa explicitly states its objectives in religious terms; the text is not only didactic but is intended to create or support an ethically inspired community in its religious program.</p

Reading the Mahavamsa

Vamsa is a dynamic genre of Buddhist history filled with otherworldly characters and the exploits of real-life heroes. These narratives collapse the temporal distance between Buddha and the reader, building an emotionally resonant connection with an outsized religious figure and a longed-for past. The fifth-century Pali text Mahāvamsa is a particularly effective example, using metaphor and other rhetorical devices to ethically transform readers, to stimulate and then to calm them. Reading the Mahāvamsa advocates a new, literary approach to this text by revealing its embedded reading advice (to experience samvega and pasada) and affective work of metaphors (the Buddha's dharma as light) and salient characters (nagas). Kristin Scheible argues that the Mahāvamsa requires a particular kind of reading. In the text’s proem, special instructions draw readers to the metaphor of light and the nagas, or salient snake-beings, of the first chapter. Nagas are both model worshippers and unworthy hoarders of Buddha’s relics. As nonhuman agents, they challenge political and historicist readings of the text. Scheible sees these slippery characters and the narrative’s potent and playful metaphors as techniques for refocusing the reader’s attention on the text’s emotional aims. Her work explains the Mahāvamsa’s central motivational role in contemporary Sri Lankan Buddhist and nationalist circles. It also speaks broadly to strategies of reading religious texts and to the internal and external cues that give such works lives beyond the page.</p